U.S. patent application number 10/994639 was filed with the patent office on 2005-05-19 for n-acetylcolchinol-o-phosphate combination therapies with vascular damaging activity.
This patent application is currently assigned to ASTRAZENECA AB. Invention is credited to Davis, Peter David, Dougherty, Graeme.
Application Number | 20050107346 10/994639 |
Document ID | / |
Family ID | 27255634 |
Filed Date | 2005-05-19 |
United States Patent
Application |
20050107346 |
Kind Code |
A1 |
Davis, Peter David ; et
al. |
May 19, 2005 |
N-acetylcolchinol-o-phosphate combination therapies with vascular
damaging activity
Abstract
The invention relates to a method for the production of a
vascular damaging effect in a warm-blooded animal such as a human,
which comprises administering to said animal an effective amount of
ZD6126 or a pharmaceutically NHCOCH acceptable salt thereof,
before, after or simultaneously with an effective amount of one of
the following therapies: i) ionising radiation; ii) a platinum
anti-tumour agent; and iii) a taxane. The invention also relates to
the use of ZD6126 and one of the above therapies in the manufacture
of a medicament for use in the production of a vascular damaging
effect in a warm-blooded animal such as a human and to
pharmaceutical compositions and kits each comprising ZD6126 and one
of a platinum anti-tumour agent and a taxane. 1
Inventors: |
Davis, Peter David; (Oxford,
GB) ; Dougherty, Graeme; (Los Angeles, CA) |
Correspondence
Address: |
MORGAN LEWIS & BOCKIUS LLP
1111 PENNSYLVANIA AVENUE NW
WASHINGTON
DC
20004
US
|
Assignee: |
ASTRAZENECA AB
|
Family ID: |
27255634 |
Appl. No.: |
10/994639 |
Filed: |
November 23, 2004 |
Current U.S.
Class: |
514/114 |
Current CPC
Class: |
A61K 41/0038 20130101;
A61K 31/661 20130101; A61P 35/00 20180101; A61K 33/243 20190101;
A61K 31/66 20130101; A61K 41/0038 20130101; A61K 33/24 20130101;
A61K 31/66 20130101; A61K 31/555 20130101; A61K 31/335 20130101;
A61K 33/24 20130101; A61K 31/66 20130101; A61K 31/335 20130101;
A61K 31/66 20130101; A61K 31/555 20130101; A61K 31/335 20130101;
A61K 31/66 20130101; A61K 2300/00 20130101; A61K 33/24 20130101;
A61K 2300/00 20130101; A61K 41/0038 20130101; A61K 2300/00
20130101 |
Class at
Publication: |
514/114 |
International
Class: |
A61K 031/66 |
Foreign Application Data
Date |
Code |
Application Number |
Mar 21, 2000 |
GB |
0007740.4 |
Jun 8, 2000 |
GB |
0013927.9 |
Jun 20, 2000 |
GB |
0014908.8 |
Claims
1-10. (canceled)
11. A method for reversing neovascularisation be damaging
newly-formed vascular endothelium in a warm-blooded animal in need
thereof, which comprises administering to said animal an effective
amount of ZD6126 3or a pharmaceutically acceptable salt thereof,
before, after or simultaneously with an effective amount of one of
the following therapies: i) ionising radiation; ii) a platinum
anti-tumour agent; and iii) a taxane.
12. A method for reversing neovascularisation by damaging
newly-formed vascular endothelium in a warm-blooded animal in need
thereof, which comprises administering to said animal an effective
amount of ZD6126 4or a pharmaceutically acceptable salt thereof, in
divided doses, before, after or simultaneously with an effective
amount of one of the following therapies: i) ionising radiation;
ii) a platinum anti-tumour agent; and iii) a taxane.
13. The method according to claim 11, which comprises administering
to said animal an effective amount of ZD6126 or a pharmaceutically
acceptable salt thereof, before, after or simultaneously with an
effective amount of ionising radiation.
14. The method according to claim 11, which comprises administering
to said animal an effective amount of ZD6126 or a pharmaceutically
acceptable salt thereof, before, after or simultaneously with an
effective amount of a platinum anti-tumour agent.
15. The method according to claim 11, which comprises administering
to said animal an effective amount of ZD6126 or a pharmaceutically
acceptable salt thereof, before, after or simultaneously with an
effective amount of a taxane.
16. A method for the treatment of a cancer involving a solid tumour
in a warm-blooded animal, which comprises administering to said
animal an effective amount of ZD6126 or a pharmaceutically
acceptable salt thereof, before, after or simultaneously with an
effective amount of ionising radiation.
17. A method for the treatment of a cancer involving a solid tumour
in a warm-blooded animal, which comprises administering to said
animal an effective amount of ZD6126 or a pharmaceutically
acceptable salt thereof, before, after or simultaneously with an
effective amount of a platinum anti-tumour agent.
18. A method for the treatment of a cancer involving a solid tumour
in a warm-blooded animal, which comprises administering to said
animal an effective amount of ZD6126 or a pharmaceutically
acceptable salt thereof, before, after or simultaneously with an
effective amount of a taxane.
19. The method according to claim 12 wherein the total daily dose
of ZD6126 is administered in two parts which are about equal or
unequal with a time interval between doses of about 1 hour to about
6 hours.
20. The method according to claim 12 wherein the total daily dose
of ZD6126 is administered in two parts which are about equal or
unequal with a time interval between doses of greater than or equal
to two hours and less than 5 hours.
21. The method according to claim 12 wherein the total daily dose
of ZD6126 is administered in two parts which are about equal or
unequal with a time interval between doses of greater than or equal
to about 2 hours and less than or equal to about 4 hours.
22. The method according to claim 12 wherein the total daily dose
of ZD6126 is administered in two parts which are about equal.
23. The method according to any one of claims 13 to 18 wherein the
ZD6126 is administered in divided doses.
24. The method according to claim 23 wherein the total dose of
ZD6126 is administered in two parts which are about equal.
25. The method according to claim 23 wherein the total daily dose
of ZD6126 is administered in two parts which are about equal or
unequal with a time interval between doses of about 1 hour to about
6 hours.
26. The method according to claim 23 wherein the total daily dose
of ZD6126 is divided into two parts which are about equal or
unequal with a time interval between doses of greater than or equal
to two hours and less than 5 hours.
27. The method according to claim 23 wherein the total daily dose
of ZD6126 is divided into two parts which are about equal or
unequal with a time interval between doses of greater than or equal
to about 2 hours and less than or equal to about 4 hours.
28. A combination treatment that produces an anti tumour effect in
a warm-blooded animal, which comprises administering to a
warm-blooded animal in need of said treatment an effective amount
of ZD6126 or a pharmaceutically acceptable salt thereof, optionally
together with a pharmaceutically acceptable excipient or carrier,
and the simultaneous, sequential or separate administration of an
effective amount of one of: i) ionising radiation; ii) a platinum
anti-tumour agent; and iii) a taxane; wherein a platinum
anti-tumour agent and a taxane may each optionally be administered
together with a pharmaceutically acceptable excipient or
carrier.
29. A combination treatment that produces an anti tumour effect in
a warm-blooded animal, which comprises administering to a
warm-blooded animal in need of said treatment an effective amount
of ZD6126 or a pharmaceutically acceptable salt thereof, optionally
together with a pharmaceutically acceptable excipient or carrier,
and the simultaneous, sequential or separate administration of an
effective amount of ionising radiation.
30. A combination treatment that produces an anti tumour effect in
a warm-blooded animal, which comprises administering to a
warm-blooded animal in need of said treatment an effective amount
of ZD6126 or a pharmaceutically acceptable salt thereof, optionally
together with a pharmaceutically acceptable excipient or carrier,
and the simultaneous, sequential or separate administration of an
effective amount of a platinum anti-tumour agent; wherein said
platinum anti-tumour agent is optionally administered together with
a pharmaceutically acceptable excipient or carrier.
31. A combination treatment that produces an anti tumour effect in
a warm-blooded animal, which comprises administering to a
warm-blooded animal in need of said treatment an effective amount
of ZD6126 or a pharmaceutically acceptable salt thereof, optionally
together with a pharmaceutically acceptable excipient or carrier,
and the simultaneous, sequential or separate administration of an
effective amount of a taxane; wherein said taxane is optionally
administered together with a pharmaceutically acceptable excipient
or carrier.
32. The combination treatment according to any one of claims 28 to
31 wherein the ZD6126 is administered in divided doses.
33. The combination treatment according to claim 32 wherein the
total daily dose of ZD6126 is administered in two parts which are
about equal.
34. The combination treatment according to claim 32 wherein the
total daily dose of ZD6126 is administered in two parts which are
about equal or unequal with a time interval between doses of about
1 hour to about 6 hours.
35. The combination treatment according to claim 32 wherein the
total daily dose of ZD6126 is administered in two parts which are
about equal or unequal with a time interval between doses of
greater than or equal to two hours and less than 5 hours.
36. The combination treatment according to claim 32 wherein the
total daily dose of ZD6126 is administered in two parts which are
about equal or unequal with a time interval between doses of
greater than or equal to about 2 hours and less than or equal to
about 4 hours.
37. The method according to any one of claims 11, 12, 14, 17, 19,
20, 21 or 22 wherein the administered therapy is a platinum
anti-tumour agent, which is selected from cisplatin, carboplatin,
oxaliplatin and
(SP-4-3)-(cis-amminedichloro[2-methylpyridine]platinum(II).
38. The method according claim 37 wherein the platinum anti-tumour
agent is cisplatin.
39. The method according to claim 14 or claim 17 wherein the ZD6126
is administered in divided doses and the platinum anti-tumour agent
is selected from cisplatin, carboplatin, oxaliplatin and
(SP-4-3)-(cis-amminedichloro[2-methylpyridine]platinum(II).
40. The method according to any one of claims 11, 12, 15, 18, 19,
20, 21 or 22 wherein the administered therapy is taxane, which is
selected from paclitaxel and docetaxel.
41. The method according to claim 40 wherein the taxane is
paclitaxel.
42. The method according to claim 15 or claim 18 wherein the ZD6126
is administered in divided doses and the taxane is selected from
paclitaxel and docetaxel.
Description
[0001] The present invention relates to a method for the production
of a vascular damaging effect in a warm-blooded animal such as a
human, particularly a method for the treatment of a cancer
involving a solid tumour, which comprises the administration of
ZD6126 in combination with one of: a platinum anti-tumour agent, a
taxane or ionising radiation; to a pharmaceutical composition
comprising ZD6126 and one of: a platinum anti-tumour agent and a
taxane; to a combination product comprising ZD6126 and one of a
platinum anti-tumour agent and a taxane for use in a method of
treatment of a human or animal body by therapy; to a kit comprising
ZD6126 and one of: a platinum anti-tumour agent and a taxane; to
the use of ZD6126 and one of: a platinum anti-tumour agent and a
taxane in the manufacture of a medicament for use in the production
of a vascular damaging effect in a warm-blooded animal such as a
human which is optionally being concomitantly treated with ionising
radiation; and to the use of ZD6126 in the manufacture of a
medicament for use in the production of a vascular damaging effect
in a warm-blooded animal such as a human which is being treated
with ionising radiation.
[0002] The present invention further relates to a method for the
production of a vascular damaging effect in a warm-blooded animal
such as a human, particularly a method for the treatment of a
cancer involving a solid tumour, which comprises the administration
of ZD6126 in divided doses, in combination with one of: a platinum
anti-tumour agent, a taxane or ionising radiation; to a combination
product comprising two or more doses of ZD6126 for administration
in divided doses, and one of a platinum anti-tumour agent and a
taxane, for use in a method of treatment of a human or animal body
by therapy; to a kit comprising two or more doses of ZD6126 for
administration in divided doses, and one of: a platinum anti-tumour
agent and a taxane; to the use of ZD6126 in the manufacture of a
medicament for use in divided doses for use in the production of a
vascular damaging effect in a warm-blooded animal such as a human
which is concomitantly treated with one of: a platinum anti-tumour
agent and a taxane; to the use of ZD6126 in the manufacture of a
medicament for use in divided doses in the production of a vascular
damaging effect in a warm-blooded animal such as a human which is
being concomitantly treated with ionising radiation.
[0003] Normal angiogenesis plays an important role in a variety of
processes including embryonic development, wound healing and
several components of female reproductive function. Undesirable or
pathological angiogenesis has been associated with disease states
including diabetic retinopathy, psoriasis, cancer, rheumatoid
arthritis, atheroma, Kaposi's sarcoma and haemangioma (Fan et al,
1995, Trends Pharmacol. Sci. 16: 57-66; Folkman, 1995, Nature
Medicine 1: 27-31). Formation of new vasculature by angiogenesis is
a key pathological feature of several diseases (J. Folkman, New
England Journal of Medicine 333, 1757-1763 (1995)). For example,
for a solid tumour to grow it must develop its own blood supply
upon which it depends critically for the provision of oxygen and
nutrients; if this blood supply is mechanically shut off the tumour
undergoes necrotic death. Neovascularisation is also a clinical
feature of skin lesions in psoriasis, of the invasive pannus in the
joints of rheumatoid arthritis patients and of atherosclerotic
plaques. Retinal neovascularisation is pathological in macular
degeneration and in diabetic retinopathy.
[0004] Reversal of neovascularisation by damaging the newly-formed
vascular endothelium is expected to have a beneficial therapeutic
effect. International Patent Application No. PCT/GB98/01977
(Publication No. WO 99/02166) describes tricyclic compounds that
surprisingly have a selective damaging effect on newly formed
vasculature as compared to the normal, established vascular
endothelium of the host species. This is a property of value in the
treatment of disease states associated with angiogenesis such as
cancer, diabetes, psoriasis, rheumatoid arthritis, Kaposi's
sarcoma, haemangioma, acute and chronic nephropathies, atheroma,
arterial restenosis, autoimmune diseases, acute inflammation,
excessive scar formation and adhesions, endometriosis,
dysfunctional uterine bleeding and ocular diseases with retinal
vessel proliferation.
[0005] Compounds which damage newly formed vasculature are vascular
damaging agents (VDAs) and are also known as vascular targeting
agents (VTAs).
[0006] One compound described in International Patent Application
No. PCT/GB98/01977 (Publication No. WO 99/02166) is
N-acetylcolchinol-O-phosp- hate, (also know as
(5S)-5-(acetylamino)-9,10,11-trimethoxy-6,7-dihydro-5H-
-dibenzo[a,c]cyclohepten-3-yl dihydrogen phosphate; Example 1 of
International Patent Application No. PCT/GB98/01977 (Publication
No. WO 99/02166)), which is referred to herein as ZD6126.
[0007] It is believed, though this is not limiting on the
invention, that ZD6126 damages newly-formed vasculature, for
example the vasculature of tumours, thus effectively reversing the
process of angiogenesis. This may be compared with other known
anti-angiogenic agents which tend to be less effective once the
vasculature has formed.
[0008] In International Patent Application No. PCT/GB98/01977
(Publication No. WO 99/02166) it is stated that:
[0009] "compounds of the invention may be administered as sole
therapy or in combination with other treatments. For the treatment
of solid tumours compounds of the invention may be administered in
combination with radiotherapy or in combination with other
anti-tumour substances for example those selected from mitotic
inhibitors, for example vinblastine, paclitaxel and docetaxel;
alkylating agents, for example cisplatin, carboplatin and
cyclophosphamide, antimetabolites, for example 5-fluorouracil,
cytosine arabinoside and hydroxyurea; intercalating agents for
example adriamycin and bleomycin; enzymes, for example
asparaginase; topoisomerase inhibitors for example etoposide,
topotecan and irinotecan; thymidylate synthase inhibitors for
example raltitrexed; biological response modifers for example
interferon; antibodies for example edrecolomab, and anti-hormones
for example tamoxifen. Such combination treatment may involve
simultaneous or sequential application of the individual components
of the treatment."
[0010] Nowhere in International Patent Application No.
PCT/GB98/01977 (Publication No. WO 99/02166) does it state that use
of any compound of the invention therein with other treatments will
produce surprisingly beneficial effects.
[0011] Unexpectedly and surprisingly we have now found that the
particular compound ZD6126 used in combination with a particular
selection of the combination therapies listed in International
Patent Application No. PCT/GB98/01977 (Publication No. WO
99/02166), namely with one of: a platinum anti-tumour agent, a
taxane and ionising radiation, produces significantly better
effects on solid tumours than any one of ZD6126, a platinum
anti-tumour agent, a taxane and ionising radiation used alone.
[0012] Anti-tumour effects of a method of treatment of the present
invention include but are not limited to, inhibition of tumour
growth, tumour growth delay, regression of tumour, shrinkage of
tumour, increased time to regrowth of tumour on cessation of
treatment, slowing of disease progression. It is expected that when
a method of treatment of the present invention is administered to a
warm-blooded animal such as a human, in need of treatment for
cancer involving a solid tumour, said method of treatment will
produce an effect, as measured by, for example, one or more of: the
extent of the anti-tumour effect, the response rate, the time to
disease progression and the survival rate.
[0013] According to another aspect of the present invention the
effect of a method of treatment of the present invention is
expected to be at least equivalent to the addition of the effects
of each of the components of said treatment used alone, that is, of
each of ZD6126 and one of: a platinum anti-tumour agent, a taxane
and ionising radiation, used alone.
[0014] According to another aspect of the present invention the
effect of a method of treatment of the present invention is
expected to be greater than the addition of the effects of each of
the components of said treatment used alone, that is, of each of
ZD6126 and one of: a platinum anti-tumour agent, a taxane and
ionising radiation, used alone.
[0015] Without being bound by theoretical considerations, it is
particularly surprising that ZD6126 in combination with a taxane
gives significantly better effects on solid tumours than ZD6126 or
a taxane used alone. This is particularly surprising because
taxanes promote assembly of microtubules and inhibit their
depolymerisation to free tubulin, (The Merck Index 1996, 12.sup.th
Edition entry nos. 7117 and 3458 for paclitaxel and docetaxel
respectively), and this would be expected to antagonise the
damaging effect of ZD6126 on newly-formed vasculature instead of
which, and unexpectedly, an enhanced anti-tumour effect is produced
when ZD6126 is used in combination with a taxane.
[0016] Unexpectedly and surprisingly we have now found that ZD6126,
when dosed in divided doses (also known as split doses) produces a
greater anti-tumour effect than when a single dose of ZD6126 is
given.
[0017] According to the present invention there is provided a
method for the production of a vascular damaging effect in a
warm-blooded animal such as a human, which comprises administering
to said animal an effective amount of ZD6126: 2
[0018] or a pharmaceutically acceptable salt thereof, before, after
or simultaneously with an effective amount of one of the following
therapies:
[0019] i) ionising radiation;
[0020] ii) a platinum anti-tumour agent; and
[0021] iii) a taxane.
[0022] According to a further aspect of the present invention there
is provided a method for the production of a vascular damaging
effect in a warm-blooded animal such as a human, which comprises
administering to said animal an effective amount of ZD6126 or a
pharmaceutically acceptable salt thereof, before, after or
simultaneously with an effective amount of ionising radiation.
[0023] According to a further aspect of the present invention there
is provided a method for the production of a vascular damaging
effect in a warm-blooded animal such as a human, which comprises
administering to said animal an effective amount of ZD6126 or a
pharmaceutically acceptable salt thereof, before, after or
simultaneously with an effective amount of a platinum anti-tumour
agent.
[0024] According to a further aspect of the present invention there
is provided a method for the production of a vascular damaging
effect in a warm-blooded animal such as a human, which comprises
administering to said animal an effective amount of ZD6126 or a
pharmaceutically acceptable salt thereof, before, after or
simultaneously with an effective amount of a taxane.
[0025] According to a further aspect of the present invention there
is provided a method for the treatment of a cancer involving a
solid tumour in a warm-blooded animal such as a human, which
comprises administering to said animal an effective amount of
ZD6126 or a pharmaceutically acceptable salt thereof, before, after
or simultaneously with an effective amount of one of the
following-therapies:
[0026] i) ionising radiation;
[0027] ii) a platinum anti-tumour agent; and
[0028] iii) a taxane.
[0029] According to a further aspect of the present invention there
is provided a method for the treatment of a cancer involving a
solid tumour in a warm-blooded animal such as a human, which
comprises administering to said animal an effective amount of
ZD6126 or a pharmaceutically acceptable salt thereof, before, after
or simultaneously with an effective amount of ionising
radiation.
[0030] According to a further aspect of the present invention there
is provided a method for the treatment of a cancer involving a
solid tumour in a warm-blooded animal such as a human, which
comprises administering to said animal an effective amount of
ZD6126 or a pharmaceutically acceptable salt thereof, before, after
or simultaneously with an effective amount of a platinum
anti-tumour agent.
[0031] According to a further aspect of the present invention there
is provided a method for the treatment of a cancer involving a
solid tumour in a warm-blooded animal such as a human, which
comprises administering to said animal an effective amount of
ZD6126 or a pharmaceutically acceptable salt thereof, before, after
or simultaneously with an effective amount of a taxane.
[0032] According to a further aspect of the present invention there
is provided a method for the production of a vascular damaging
effect in a warm-blooded animal such as a human, which comprises
administering to said animal an effective amount of ZD6126 or a
pharmaceutically acceptable salt thereof, before, after or
simultaneously with an effective amount of one of the following
therapies:
[0033] i) ionising radiation;
[0034] ii) a platinum anti-tumour agent; and
[0035] iii) a taxane;
[0036] wherein ZD6126, a platinum anti-tumour agent and a taxane
may each optionally be administered together with a
pharmaceutically acceptable excipient or carrier.
[0037] According to a further aspect of the present invention there
is provided a method for the production of a vascular damaging
effect in a warm-blooded animal such as a human, which comprises
administering to said animal an effective amount of ZD6126 or a
pharmaceutically acceptable salt thereof, before, after or
simultaneously with an effective amount of ionising radiation
wherein ZD6126 may optionally be administered together with a
pharmaceutically acceptable excipient or carrier.
[0038] According to a further aspect of the present invention there
is provided a method for the production of a vascular damaging
effect in a warm-blooded animal such as a human, which comprises
administering to said animal an effective amount of ZD6126 or a
pharmaceutically acceptable salt thereof, before, after or
simultaneously with an effective amount of a platinum anti-tumour
agent wherein ZD6126 and a platinum anti-tumour agent may each
optionally be administered together with a pharmaceutically
acceptable excipient or carrier.
[0039] According to a further aspect of the present invention there
is provided a method for the production of a vascular damaging
effect in a warm-blooded animal such as a hum-an, which comprises
administering to said animal an effective amount of ZD6126 or a
pharmaceutically acceptable salt thereof, before, after or
simultaneously with an effective amount of a taxane wherein ZD6126
and a taxane may each optionally be administered together with a
pharmaceutically acceptable excipient or carrier.
[0040] According to a further aspect of the present invention there
is provided a method for the treatment of a cancer involving a
solid tumour in a warm-blooded animal such as a human, which
comprises administering to said animal an effective amount of
ZD6126 or a pharmaceutically acceptable salt thereof, before, after
or simultaneously with an effective amount of one of the following
therapies:
[0041] i) ionising radiation;
[0042] ii) a platinum anti-tumour agent; and
[0043] iii) a taxane;
[0044] wherein ZD6126, a platinum anti-tumour agent and a taxane
may each optionally be administered together with a
pharmaceutically acceptable excipient or carrier.
[0045] According to a further aspect of the present invention there
is provided a method for the treatment of a cancer involving a
solid tumour in a warm-blooded animal such as a human, which
comprises administering to said animal an effective amount of
ZD6126 or a pharmaceutically acceptable salt thereof, before, after
or simultaneously with an effective amount of ionising radiation
wherein ZD6126 may optionally be administered together with a
pharmaceutically acceptable excipient or carrier.
[0046] According to a further aspect of the present invention there
is provided a method for the treatment of a cancer involving a
solid tumour in a warm-blooded animal such as a human, which
comprises administering to said animal an effective amount of
ZD6126 or a pharmaceutically acceptable salt thereof, before, after
or simultaneously with an effective amount of a platinum
anti-tumour agent wherein ZD6126 and a platinum anti-tumour agent
may each optionally be administered together with a
pharmaceutically acceptable excipient or carrier.
[0047] According to a further aspect of the present invention there
is provided a method for the treatment of a cancer involving a
solid tumour in a warm-blooded animal such as a human, which
comprises administering to said animal an effective amount of
ZD6126 or a pharmaceutically acceptable salt thereof, before, after
or simultaneously with an effective amount of a taxane wherein
ZD6126 and a taxane may each optionally be administered together
with a pharmaceutically acceptable excipient or carrier.
[0048] According to a further aspect of the invention there is
provided a pharmaceutical composition which comprises ZD6126 or a
pharmaceutically acceptable salt thereof, and a platinum
anti-tumour agent in association with a pharmaceutically acceptable
excipient or carrier.
[0049] According to a further aspect of the invention there is
provided a pharmaceutical composition which comprises ZD6126 or a
pharmaceutically acceptable salt thereof, and a taxane in
association with a pharmaceutically acceptable excipient or
carrier.
[0050] According to a further aspect of the present invention there
is provided a combination product comprising ZD6126 or a
pharmaceutically acceptable salt thereof and one of: a platinum
anti-tumour agent and a taxane, for use in a method of treatment of
a human or animal body by therapy.
[0051] According to a further aspect of the present invention there
is provided a combination product comprising ZD6126 or a
pharmaceutically acceptable salt thereof and a platinum anti-tumour
agent, for use in a method of treatment of a human or animal body
by therapy.
[0052] According to a further aspect of the present invention there
is provided a combination product comprising ZD6126 or a
pharmaceutically acceptable salt thereof and a taxane, for use in a
method of treatment of a human or animal body by therapy.
[0053] According to a further aspect of the present invention there
is provided a kit comprising ZD6126 or a pharmaceutically
acceptable salt thereof, and one of: a platinum anti-tumour agent
and a taxane.
[0054] According to a further aspect of the present invention there
is provided a kit comprising ZD6126 or a pharmaceutically
acceptable salt thereof, and a platinum anti-tumour agent.
[0055] According to a further aspect of the present invention there
is provided a kit comprising ZD6126 or a pharmaceutically
acceptable salt thereof, and a taxane.
[0056] According to a further aspect of the present invention there
is provided a kit comprising:
[0057] a) ZD6126 or a pharmaceutically acceptable salt thereof in a
first unit dosage form;
[0058] b) one of: a platinum anti-tumour agent and a taxane in a
second unit dosage form; and
[0059] c) container means for containing said first and second
dosage forms.
[0060] According to a further aspect of the present invention there
is provided a kit comprising:
[0061] a) ZD6126 or a pharmaceutically acceptable salt thereof in a
first unit dosage form;
[0062] b) a platinum anti-tumour agent in a second unit dosage
form; and
[0063] c) container means for containing said first and second
dosage forms.
[0064] According to a further aspect of the present invention there
is provided a kit comprising:
[0065] a) ZD6126 or a pharmaceutically acceptable salt thereof in a
first unit dosage form;
[0066] b) a taxane in a second unit dosage form, and
[0067] c) container means for containing said first and second
dosage forms.
[0068] According to a further aspect of the present invention there
is provided a kit comprising:
[0069] a) ZD6126 or a pharmaceutically acceptable salt thereof,
together with a pharmaceutically acceptable excipient or carrier,
in a first unit dosage form;
[0070] b) one of: a platinum anti-tumour agent and a taxane,
together with a pharmaceutically acceptable excipient or carrier,
in a second unit dosage form; and
[0071] c) container means for containing said first and second
dosage forms.
[0072] According to a further aspect of the present invention there
is provided a kit comprising:
[0073] a) ZD6126 or a pharmaceutically acceptable salt thereof,
together with a pharmaceutically acceptable excipient or carrier,
in a first unit dosage form;
[0074] b) a platinum anti-tumour agent together with a
pharmaceutically acceptable excipient or carrier, in a second unit
dosage form; and
[0075] c) container means for containing said first and second
dosage forms.
[0076] According to a further aspect of the present invention there
is provided a kit comprising:
[0077] a) ZD6126 or a pharmaceutically acceptable salt thereof,
together with a pharmaceutically acceptable excipient or carrier,
in a first unit dosage form;
[0078] b) a taxane together with a pharmaceutically acceptable
excipient or carrier, in a second unit dosage form; and
[0079] c) container means for containing said first and second
dosage forms.
[0080] According to a further aspect of the present invention there
is provided the use of ZD6126 or a pharmaceutically acceptable salt
thereof and one of: a platinum anti-tumour agent and a taxane, in
the manufacture of a medicament for use in the production of a
vascular damaging effect in a warm-blooded animal such as a
human.
[0081] According to a further aspect of the present invention there
is provided the use of ZD6126 or a pharmaceutically acceptable salt
thereof and a platinum anti-tumour agent in the manufacture of a
medicament for use in the production of a vascular damaging effect
in a warm-blooded animal such as a human.
[0082] According to a further aspect of the present invention there
is provided the use of ZD6126 or a pharmaceutically acceptable salt
thereof and a taxane in the manufacture of a medicament for use in
the production of a vascular damaging effect in a warm-blooded
animal such as a human.
[0083] According to a further aspect of the present invention there
is provided the use of ZD6126 or a pharmaceutically acceptable salt
thereof and one of: a platinum anti-tumour agent and a taxane, in
the manufacture of a medicament for use in the production of an
anti-cancer effect in a warm-blooded animal such as a human.
[0084] According to a further aspect of the present invention there
is provided the use of ZD6126 or a pharmaceutically acceptable salt
thereof and a platinum anti-tumour agent in the manufacture of a
medicament for use in the production of an anti-cancer effect in a
warm-blooded animal such as a human.
[0085] According to a further aspect of the present invention there
is provided the use of ZD6126 or a pharmaceutically acceptable salt
thereof and a taxane in the manufacture of a medicament for use in
the production of an anti-cancer effect in a warm-blooded animal
such as a human.
[0086] According to a further aspect of the present invention there
is provided the use of ZD6126 or a pharmaceutically acceptable salt
thereof and one of: a platinum anti-tumour agent and a taxane, in
the manufacture of a medicament for use in the production of an
anti-tumour effect in a warm-blooded animal such as a human.
[0087] According to a further aspect of the present invention there
is provided the use of ZD6126 or a pharmaceutically acceptable salt
thereof and a platinum anti-tumour agent in the manufacture of a
medicament for use in the production of an anti-tumour effect in a
warm-blooded animal such as a human.
[0088] According to a further aspect of the present invention there
is provided the use of ZD6126 or a pharmaceutically acceptable salt
thereof and a taxane in the manufacture of a medicament for use in
the production of an anti-tumour effect in a warm-blooded animal
such as a human.
[0089] According to a further aspect of the present invention there
is provided the use of ZD6126 or a pharmaceutically acceptable salt
thereof in the manufacture of a medicament for use in the
production of a vascular damaging effect in a warm-blooded animal
such as a human which is being treated with ionising radiation.
[0090] According to a further aspect of the present invention there
is provided the use of ZD6126 or a pharmaceutically acceptable salt
thereof in the manufacture of a medicament for use in the
production of an anti-cancer effect in a warm-blooded animal such
as a human which is being treated with ionising radiation.
[0091] According to a further aspect of the present invention there
is provided the use of ZD6126 or a pharmaceutically acceptable salt
thereof in the manufacture of a medicament for use in the
production of an anti-tumour effect in a warm-blooded animal such
as a human which is being treated with ionising radiation.
[0092] A warm-blooded animal such as a human which is being treated
with ionising radiation means a warm-blooded animal such as a human
which is treated with ionising radiation before, after or at the
same time as the administration of a medicament comprising ZD6126.
For example said ionising radiation may be given to said
warm-blooded animal such as a human within the period of a week
before to a week after the administration of a medicament
comprising ZD6126.
[0093] According to a further aspect of the present invention there
is provided a combination treatment comprising the administration
of an effective amount of ZD6126 or a pharmaceutically acceptable
salt thereof, optionally together with a pharmaceutically
acceptable excipient or carrier, and the simultaneous, sequential
or separate administration of an effective amount of one of:
[0094] i) ionising radiation;
[0095] ii) a platinum anti-tumour agent; and
[0096] iii) a taxane;
[0097] wherein a platinum anti-tumour agent and a taxane may each
optionally be administered together with a pharmaceutically
acceptable excipient or carrier;
[0098] to a warm-blooded animal such as a human in need of such
therapeutic treatment.
[0099] Such therapeutic treatment includes a vascular damaging
effect, an anti-cancer effect and an anti-tumour effect.
[0100] According to a further aspect of the present invention there
is provided a combination treatment comprising the administration
of an effective amount of ZD6126 or a pharmaceutically acceptable
salt thereof, optionally together with a pharmaceutically
acceptable excipient or carrier, and the simultaneous, sequential
or separate administration of an effective amount of ionising
radiation to a warm-blooded animal such as a human in need of such
therapeutic treatment.
[0101] According to a further aspect of the present invention there
is provided a combination treatment comprising the administration
of an effective amount of ZD6126 or a pharmaceutically acceptable
salt thereof, optionally together with a pharmaceutically
acceptable excipient or carrier, and the simultaneous, sequential
or separate administration of an effective amount of a platinum
anti-tumour agent, wherein a platinum anti-tumour agent may
optionally be administered together with a pharmaceutically
acceptable excipient or carrier, to a warm-blooded animal such as a
human in need of such therapeutic treatment.
[0102] According to a further aspect of the present invention there
is provided a combination treatment comprising the administration
of an effective amount of ZD6126 or a pharmaceutically acceptable
salt thereof, optionally together with a pharmaceutically
acceptable excipient or carrier, and the simultaneous, sequential
or separate administration of an effective amount of a taxane,
wherein a taxane may optionally be administered together with a
pharmaceutically acceptable excipient or carrier, to a warm-blooded
animal such as a human in need of such therapeutic treatment.
[0103] According to a further aspect of the present invention there
is provided a method for the production of a vascular damaging
effect in a warm-blooded animal such as a human, which comprises
administering to said animal an effective amount of ZD6126 or a
pharmaceutically acceptable salt thereof, in divided doses, before,
after or simultaneously with an effective amount of one of the
following therapies:
[0104] i) ionising radiation;
[0105] ii) a platinum anti-tumour agent; and
[0106] iii) a taxane.
[0107] According to a further aspect of the present invention there
is provided a method for the production of a vascular damaging
effect in a warm-blooded animal such as a human, which comprises
administering to said animal an effective amount of ZD6126 or a
pharmaceutically acceptable salt thereof, in divided doses, before,
after or simultaneously with an effective amount of ionising
radiation.
[0108] According to a further aspect of the present invention there
is provided a method for the production of a vascular damaging
effect in a warm-blooded animal such as a human, which comprises
administering to said animal an effective amount of ZD6126 or a
pharmaceutically acceptable salt thereof, in divided doses, before,
after or simultaneously with an effective amount of a platinum
anti-tumour agent.
[0109] According to a further aspect of the present invention there
is provided a method for the production of a vascular damaging
effect in a warm-blooded animal such as a human, which comprises
administering to said animal an effective amount of ZD6126 or a
pharmaceutically acceptable salt thereof, in divided doses, before,
after or simultaneously with an effective amount of a taxane.
[0110] According to a further aspect of the present invention there
is provided a method for the treatment of a cancer involving a
solid tumour in a warm-blooded animal such as a human, which
comprises administering to said animal an effective amount of
ZD6126 or a pharmaceutically acceptable salt thereof, in divided
doses, before, after or simultaneously with an effective amount of
one of the following therapies:
[0111] i) ionising radiation;
[0112] ii) a platinum anti-tumour agent; and
[0113] iii) a taxane.
[0114] According to a further aspect of the present invention there
is provided a method for the treatment of a cancer involving a
solid tumour in a warm-blooded animal such as a human, which
comprises administering to said animal an effective amount of
ZD6126 or a pharmaceutically acceptable salt thereof, in divided
doses, before, after or simultaneously with an effective amount of
ionising radiation.
[0115] According to a further aspect of the present invention there
is provided a method for the treatment of a cancer involving a
solid tumour in a warm-blooded animal such as a human, which
comprises administering to said animal an effective amount of
ZD6126 or a pharmaceutically acceptable salt thereof, in divided
doses, before, after or simultaneously with an effective amount of
a platinum anti-tumour agent.
[0116] According to a further aspect of the present invention there
is provided a method for the treatment of a cancer involving a
solid tumour in a warm-blooded animal such as a human, which
comprises administering to said animal an effective amount of
ZD6126 or a pharmaceutically acceptable salt thereof, in divided
doses, before, after or simultaneously with an effective amount of
a taxane.
[0117] According to a further aspect of the present invention there
is provided a method for the production of a vascular damaging
effect in a warm-blooded animal such as a human, which comprises
administering to said animal an effective amount of ZD6126 or a
pharmaceutically acceptable salt thereof, in divided doses, before,
after or simultaneously with an effective amount of one of the
following therapies:
[0118] i) ionising radiation;
[0119] ii) a platinum anti-tumour agent; and
[0120] iii) a taxane;
[0121] wherein ZD6126, a platinum anti-tumour agent and a taxane
may each optionally be administered together with a
pharmaceutically acceptable excipient or carrier.
[0122] According to a further aspect of the present invention there
is provided a method for the production of a vascular damaging
effect in a warm-blooded animal such as a human, which comprises
administering to said animal an effective amount of ZD6126 or a
pharmaceutically acceptable salt thereof, in divided doses, before,
after or simultaneously with an effective amount of ionising
radiation wherein ZD6126 may optionally be administered together
with a pharmaceutically acceptable excipient or carrier.
[0123] According to a further aspect of the present invention there
is provided a method for the production of a vascular damaging
effect in a warm-blooded animal such as a human, which comprises
administering to said animal an effective amount of ZD6126 or a
pharmaceutically acceptable salt thereof, in divided doses, before,
after or simultaneously with an effective amount of a platinum
anti-tumour agent wherein ZD6126 and a platinum anti-tumour agent
may each optionally be administered together with a
pharmaceutically acceptable excipient or carrier.
[0124] According to a further aspect of the present invention there
is provided a method for the production of a vascular damaging
effect in a warm-blooded animal such as a human, which comprises
administering to said animal an effective amount of ZD6126 or a
pharmaceutically acceptable salt thereof, in divided doses, before,
after or simultaneously with an effective amount of a taxane
wherein ZD6126 and a taxane may each optionally be administered
together with a pharmaceutically acceptable excipient or
carrier.
[0125] According to a further aspect of the present invention there
is provided a method for the treatment of a cancer involving a
solid tumour in a warm-blooded animal such as a human, which
comprises administering to said animal an effective amount of
ZD6126 or a pharmaceutically acceptable salt thereof, in divided
doses, before, after or simultaneously with an effective amount of
one of the following therapies:
[0126] i) ionising radiation;
[0127] ii) a platinum anti-tumour agent; and
[0128] iii) a taxane;
[0129] wherein ZD6126, a platinum anti-tumour agent and a taxane
may each optionally be administered together with a
pharmaceutically acceptable excipient or carrier.
[0130] According to a further aspect of the present invention there
is provided a method for the treatment of a cancer involving a
solid tumour in a warm-blooded animal such as a human, which
comprises administering to said animal an effective amount of
ZD6126 or a pharmaceutically acceptable salt thereof, in divided
doses, before, after or simultaneously with an effective amount of
ionising radiation wherein ZD6126 may optionally be administered
together with a pharmaceutically acceptable excipient or
carrier.
[0131] According to a further aspect of the present invention there
is provided a method for the treatment of a cancer involving a
solid tumour in a warm-blooded animal such as a human, which
comprises administering to said animal an effective amount of
ZD6126 or a pharmaceutically acceptable salt thereof, in divided
doses, before, after or simultaneously with an effective amount of
a platinum anti-tumour agent wherein ZD6126 and a platinum.
anti-tumour agent may each optionally be administered together with
a pharmaceutically acceptable excipient or carrier.
[0132] According to a further aspect of the present invention there
is provided a method for the treatment of a cancer involving a
solid tumour in a warm-blooded animal such as a human, which
comprises administering to said animal an effective amount of
ZD6126 or a pharmaceutically acceptable salt thereof, in divided
doses, before, after or simultaneously with an effective amount of
a taxane wherein ZD6126 and a taxane may each optionally be
administered together with a pharmaceutically acceptable excipient
or carrier.
[0133] According to a further aspect of the present invention there
is provided a combination product comprising two or more fractions
of doses of ZD6126 or a pharmaceutically acceptable salt thereof,
which together add up to a total daily dose, for administration in
divided doses, and one of: a platinum anti-tumour agent and a
taxane, for use in a method of treatment of a human or animal body
by therapy.
[0134] According to a further aspect of the present invention there
is provided a combination product comprising two or more fractions
of doses of ZD6126 or a pharmaceutically acceptable salt thereof,
which together add up to a total daily dose, for administration in
divided doses, and a platinum anti-tumour agent, for use in a
method of treatment of a human or animal body by therapy.
[0135] According to a further aspect of the present invention there
is provided a combination product comprising two or more fractions
of doses of ZD6126 or a pharmaceutically acceptable salt thereof,
which together add up to a total daily dose, for administration in
divided doses, and a taxane, for use in a method of treatment of a
human or animal body by therapy.
[0136] According to a further aspect of the present invention there
is provided a kit comprising two or more fractions of doses of
ZD6126 or a pharmaceutically acceptable salt thereof, which
together add up to a total daily dose, for administration in
divided doses, and one of: a platinum anti-tumour agent and a
taxane.
[0137] According to a further aspect of the present invention there
is provided a kit comprising two or more fractions of doses of
ZD6126 or a pharmaceutically acceptable salt thereof, which
together add up to a total daily dose, for administration in
divided doses, and a platinum anti-tumour agent.
[0138] According to a further aspect of the present invention there
is provided a kit comprising two or more fractions of doses of
ZD6126 or a pharmaceutically acceptable salt thereof, which
together add up to a total daily dose, for administration in
divided doses, and a taxane.
[0139] According to a further aspect of the present invention there
is provided a kit comprising:
[0140] a) two or more fractions of doses of ZD6126 or a
pharmaceutically acceptable salt thereof, which together add up to
a total daily dose, in first unit dosage forms for administration
in divided doses;
[0141] b) one of: a platinum anti-tumour agent and a taxane in a
second unit dosage form; and
[0142] c) container means for containing said first and second
dosage forms.
[0143] According to a further aspect of the present invention there
is provided a kit comprising:
[0144] a) two or more fractions of doses of ZD6126 or a
pharmaceutically acceptable salt thereof, which together add up to
a total daily dose, in first unit dosage forms for administration
in divided doses;
[0145] b) a platinum anti-tumour agent in a second unit dosage
form; and
[0146] c) container means for containing said first and second
dosage forms.
[0147] According to a further aspect of the present invention there
is provided a kit comprising:
[0148] a) two or more fractions of doses of ZD6126 or a
pharmaceutically acceptable salt thereof, which together add up to
a total daily dose, in first unit dosage forms for administration
in divided doses;
[0149] b) a taxane in a second unit dosage form; and
[0150] c) container means for containing said first and second
dosage forms.
[0151] According to a further aspect of the present invention there
is provided a kit comprising:
[0152] a) two or more fractions of doses of ZD6126 or a
pharmaceutically acceptable salt thereof, which together add up to
a total daily dose, together with a pharmaceutically acceptable
excipient or carrier, in first unit dosage forms for administration
in divided doses;
[0153] b) one of: a platinum anti-tumour agent and a taxane,
together with a pharmaceutically acceptable excipient or carrier,
in a second unit dosage form; and
[0154] c) container means for containing said first and second
dosage forms.
[0155] According to a further aspect of the present invention there
is provided a kit comprising:
[0156] a) two or more fractions of doses of ZD6126 or a
pharmaceutically acceptable salt thereof, which together add up to
a total daily dose, together with a pharmaceutically acceptable
excipient or carrier, in first unit dosage forms for administration
in divided doses;
[0157] b) a platinum anti-tumour agent together with a
pharmaceutically acceptable excipient or carrier, in a second unit
dosage form; and
[0158] c) container means for containing said first and second
dosage forms.
[0159] According to a further aspect of the present invention there
is provided a kit comprising:
[0160] a) two or more fractions of doses of ZD6126 or a
pharmaceutically acceptable salt thereof, which together add up to
a total daily dose, together with a pharmaceutically acceptable
excipient or carrier, in first unit dosage forms for administration
in divided doses;
[0161] b) a taxane, together with a pharmaceutically acceptable
excipient or carrier, in a second unit dosage form; and
[0162] c) container means for containing said first and second
dosage forms.
[0163] According to a further aspect of the present invention there
is provided the use of ZD6126 or a pharmaceutically acceptable salt
thereof in the manufacture of a medicament for use when
administered in divided doses in the production of a vascular
damaging effect in a warm-blooded animal such as a human which is
being treated with ionising radiation.
[0164] According to a further aspect of the present invention there
is provided the use of ZD6126 or a pharmaceutically acceptable salt
thereof in the manufacture of a medicament for use when
administered in divided doses in the production of an anti-cancer
effect in a warm-blooded animal such as a human which is being
treated with ionising radiation.
[0165] According to a further aspect of the present invention there
is provided the use of ZD6126 or a pharmaceutically acceptable salt
thereof in the manufacture of a medicament for use when
administered in divided doses in the production of an anti-tumour
effect in a warm-blooded animal such as a human which is being
treated with ionising radiation.
[0166] According to a further aspect of the present invention there
is provided a combination treatment comprising the administration
in divided doses of an effective amount of ZD6126 or a
pharmaceutically acceptable salt thereof, optionally together with
a pharmaceutically acceptable excipient or carrier, and the
simultaneous, sequential or separate administration of an effective
amount of one of:
[0167] i) ionising radiation;
[0168] ii) a platinum anti-tumour agent; and
[0169] iii) a taxane;
[0170] wherein a platinum anti-tumour agent and a taxane may each
optionally be administered together with a pharmaceutically
acceptable excipient or carrier;
[0171] to a warm-blooded animal such as a human in need of such
therapeutic treatment.
[0172] Such therapeutic treatment includes a vascular damaging
effect, an anti-cancer effect and an anti-tumour effect.
[0173] According to a further aspect of the present invention there
is provided a combination treatment comprising the administration
in divided doses of an effective amount of ZD6126 or a
pharmaceutically acceptable salt thereof, optionally together with
a pharmaceutically acceptable excipient or carrier, and the
simultaneous, sequential or separate administration of an effective
amount of ionising radiation to a warm-blooded animal such as a
human in need of such therapeutic treatment.
[0174] According to a further aspect of the present invention there
is provided a combination treatment comprising the administration
in divided doses of an effective amount of ZD6126 or a
pharmaceutically acceptable salt thereof, optionally together with
a pharmaceutically acceptable excipient or carrier, and the
simultaneous, sequential or separate administration of an effective
amount of a platinum anti-tumour agent wherein said platinum
anti-tumour agent may optionally be administered together with a
pharmaceutically acceptable excipient or carrier, to a warm-blooded
animal such as a human in need of such therapeutic treatment.
[0175] According to a further aspect of the present invention there
is provided a combination treatment comprising the administration
in divided doses of an effective amount of ZD6126 or a
pharmaceutically acceptable salt thereof, optionally together with
a pharmaceutically acceptable excipient or carrier, and the
simultaneous, sequential or separate administration of an effective
amount of a taxane wherein said taxane may optionally be
administered together with a pharmaceutically acceptable excipient
or carrier, to a warm-blooded animal such as a human in need of
such therapeutic treatment.
[0176] As stated above the combination treatments of the present
invention as defined herein are of interest for their vascular
damaging effects. Such combination treatments of the invention are
expected to be useful in the prophylaxis and treatment of a wide
range of disease states where inappropriate angiogenesis occurs
including cancer, diabetes, psoriasis, rheumatoid arthritis,
Kaposi's sarcoma, haemangioma, acute and chronic nephropathies,
atheroma, arterial restenosis, autoimmune diseases, acute
inflammation, endometriosis, dysfunctional uterine bleeding and
ocular diseases with retinal vessel proliferation. In particular
such combination treatments of the invention are expected to slow
advantageously the growth of primary and recurrent solid tumours
of, for example, the colon, breast, prostate, lungs and skin.
[0177] A combination treatment of the present invention as defined
herein may be achieved by way of the simultaneous, sequential or
separate administration of the individual components of said
treatment. A combination treatment as defined herein may be applied
as a sole therapy or may involve surgery, in addition to a
combination treatment of the invention. Surgery may comprise the
step of partial or complete tumour resection, prior to, during or
after the administration of the combination treatment with ZD6126
described herein.
[0178] The compositions described herein may be in a form suitable
for oral administration, for example as a tablet or capsule, for
nasal administration or administration by inhalation, for example
as a powder or solution, for parenteral injection (including
intravenous, subcutaneous, intramuscular, intravascular or
infusion) for example as a sterile solution, suspension or
emulsion, for topical administration for example as an ointment or
cream, for rectal administration for example as a suppository or
the route of administration may be by direct injection into the
tumour or by regional delivery or by local delivery. In other
embodiments of the present invention the ZD6126 of the combination
treatment may be delivered endoscopically, intratracheally,
intralesionally, percutaneously, intravenously, subcutaneously,
intraperitoneally or intratumourally. In general the compositions
described herein may be prepared in a conventional manner using
conventional excipients. The compositions of the present invention
are advantageously presented in unit dosage form.
[0179] ZD6126 will normally be administered to a warm-blooded
animal at a unit dose within the range 10-500 mg per square metre
body area of the animal, for example approximately 0.3-15 mg/kg in
a human. A unit dose in the range, for example, 0.3-15 mg/kg,
preferably 0.5-5 mg/kg is envisaged and this is normally a
therapeutically-effective dose. A unit dosage form such as a tablet
or capsule will usually contain, for example 25-250 mg of active
ingredient. Preferably a daily dose in the range of 0.5-5 mg/kg is
employed.
[0180] Divided doses, also called split doses, means that the total
dose to be administered to a warm-blooded animal, such as a human,
in any one day period (for example one 24 hour period from midnight
to midnight) is divided up into two or more fractions of the total
dose and these fractions are administered with a time period
between each fraction of about greater than 0 hours to about 10
hours, preferably about 1 hour to about 6 hours, more preferably
about 2 hours to about 4 hours. The fractions of total dose may be
about equal or unequal. Preferably the total dose is divided into
two parts which may be about equal or unequal. The time intervals
between doses may be for example selected from:
[0181] about 1 hour, about 1.5 hours, about 2 hours, about 2.5
hours, about 3 hours, about 3.5 hours, about 4 hours, about 4.5
hours, about 5 hours, about 5.5 hours and about 6 hours.
[0182] The time intervals between doses may be any number
(including non-integers) of minutes between greater than 0 minutes
and 600 minutes, preferably between 45 and 375 minutes inclusive.
If more than two doses are administered the time intervals between
each dose may be about equal or unequal.
[0183] Preferably two doses are given with a time interval in
between them of greater than or equal to 1 hour and less than 6
hours.
[0184] More preferably two doses are given with a time interval in
between them of greater than or equal to two hours and less than 5
hours.
[0185] Yet more preferably two doses are given with a time interval
in between them of greater than or equal to two hours and less than
or equal to 4 hours.
[0186] Particularly the total dose is divided into two parts which
may be about equal or unequal with a time interval between doses of
greater than or equal to about two hours and less than or equal to
about 4 hours.
[0187] More particularly the total dose is divided into two parts
which may be about equal with a time interval between doses of
greater than or equal to two hours and less than or equal to 4
hours.
[0188] For the avoidance of doubt the term `about` in the
description of time periods means the time given plus or minus 15
minutes, thus for example about 1 hour means 45 to 75 minutes,
about 1.5 hours means 75 to 105 minutes. Elsewhere the term `about`
has its usual dictionary meaning.
[0189] Platinum anti-tumour agents include cisplatin, carboplatin,
oxaliplatin and
(SP-4-3)-cis-amminedichloro[2-methylpyridine]platinum(II)- ,
otherwise known as ZD0473.
[0190] Taxanes include paclitaxel and docetaxel.
[0191] Platinum anti-tumour agents and taxanes may be dosed
according to known routes of administration and dosages.
[0192] For example cisplatin may be administered as a single
intravenous infusion over a period of 6-8 hours at a dose of 40-120
mg/m.sup.2 every 3-4 weeks. Alternatively for example cisplatin may
be administered as a single intravenous infusion over a period of
6-8 hours at a dose of 15-20 mg/m.sup.2 daily for up to 5 days
every 3-4 weeks.
[0193] For example carboplatin may be administered as a single
short-term intravenous infusion over a period of 15-60 minutes at a
dose of 250-400 mg/m.sup.2 every 4 weeks.
[0194] For example oxaliplatin may be administered by intravenous
infusion over a period of 2-6 hours at a dose of about 85
mg/m.sup.2 every 2 weeks.
[0195] For example paclitaxel may be administered as an infusion
over a period of about 24 hours at a dose of 135-200 mg/m.sup.2
every 3 weeks. Alternatively for example paclitaxel may be
administered as an infusion over a period of about 3 hours at a
dose of 135-225 mg/m.sup.2 every 3 weeks. Alternatively for example
paclitaxel may be administered as an infusion over a period of
about 1 hour at a dose of 80-100 mg/m.sup.2 every week for a number
of weeks. Alternatively for example paclitaxel may be administered
as an infusion over a period of about 1 hour at a dose of 200
mg/m.sup.2 every 3 weeks. Alternatively for example paclitaxel may
be administered as an infusion over a period of about 96 hours at a
dose of 120-140 mg/m.sup.2 every 3 weeks.
[0196] Docetaxel may be dosed in according with known routes of
administration and dosages. For example docetaxel may be
administered as an infusion over a period of 1 hour at a dose of
55-100 mg/m.sup.2 every 3 weeks.
[0197] In particular embodiments of the present invention the
ionising radiation employed may be X-radiation, .gamma.-radiation
or .beta.-radiation.
[0198] The dosages of ionising radiation will be those known for
use in clinical radiotherapy. The radiation therapy used will
include for example the use of .gamma.-rays, X-rays, and/or the
directed delivery of radiation from radioisotopes. Other forms of
DNA damaging factors are also included in the present invention
such as microwaves and UV-irradiation. It is most likely that all
of these factors effect a broad range of damage on DNA, on the
precursors of DNA, on the replication and repair of DNA and on the
assembly and maintenance of chromosomes. For example X-rays may be
dosed in daily doses of 1.8-2.0 Gy, 5 days a week for 5-6 weeks.
Normally a total fractionated dose will lie in the range 45-60 Gy.
Single larger doses, for example 5-10 Gy may be administered as
part of a course of radiotherapy. Single doses may be administered
intraoperatively. Hyperfractionated radiotherapy may be used
whereby small doses of X-rays are administered regularly over a
period of time, for example 0.1 Gy per hour over a number of days.
Dosage ranges for radioisotopes vary widely, and depend on the
half-life of the isotope, the strength and type of radiation
emitted, and on the uptake by cells.
[0199] As stated above the size of the dose of each therapy which
is required for the therapeutic or prophylactic treatment of a
particular disease state will necessarily be varied depending on
the host treated, the route of administration and the severity of
the illness being treated. Accordingly the optimum dosage may be
determined by the practitioner who is treating any particular
patient. For example, it may be necessary or desirable to reduce
the above-mentioned doses of the components of the combination
treatments in order to reduce toxicity.
[0200] The present invention relates to combinations of ionising
radiation, cisplatin or paclitaxel or docetaxel with ZD6126 or with
a salt of ZD6126. Salts for use in pharmaceutical compositions will
be pharmaceutically acceptable salts, but other salts may be useful
in the production of ZD6126 and its pharmaceutically acceptable
salts. Such salts may be formed with an inorganic or organic base
which affords a pharmaceutically acceptable cation. Such salts with
inorganic or organic bases include for example an alkali metal
salt, such as a sodium or potassium salt, an alkaline earth metal
salt such as a calcium or magnesium salt, an ammonium salt or for
example a salt with methylamine, dimethylamine, trimethylamine,
piperidine, morpholine or tris-2-hydroxyethyl)amine.
[0201] ZD6126 may be made according to the following process.
[0202] N-Acetylcolchinol (30.0 g, 83.9 mmol) is dissolved in
acetonitrile under an inert atmosphere and 1,2,3-triazole (14.67 g,
212.4 mmol) added via a syringe.
Di-tert-butyl-diethylphosphoramidite (37.7 g, 151.4 mmol) is added
and the reaction mixture stirred at about 20.degree. C. to complete
the formation of the intermediate phosphite ester. Cumene
hydroperoxide (24.4 g, 159.2 mmol) is added at about 10.degree. C.
and the reaction mixture stirred until the oxidation is complete.
Butyl acetate (50 ml) and sodium hydroxide solution (250 ml of 1M)
are added, the reaction mixture stirred and the aqueous phase
discarded. The organic solution is washed with sodium hydroxide
solution (2.times.250 ml of 1M) and a saturated solution of sodium
chloride. Trifluoroacetic acid (95.3 g, 836 mmol) is added at about
15.degree. C. The reaction mixture is distilled at atmospheric
pressure, ZD6126 crystallises and is isolated at ambient
temperature.
[0203] The following tests were used to demonstrate the activity of
ZD6126 in combination with cisplatin, paclitaxel or ionising
radiation.
[0204] ZD6126 in Combination with Cisplatin
[0205] a) CaNT Tumour Model
[0206] In the murine adenocarcinoma CaNT tumour model grown in
female CBA mice (Hill, S. A. et al, Int. J. Cancer 63, 119-123,
1995) combining ZD6126 and cisplatin resulted in significantly
improved growth delay compared to either agent alone.
[0207] (i) First Study
[0208] ZD6126 alone was dosed on days 0, 2 and 4 using a split dose
regimen of 100 mg/kg ZD6126, followed by a 2 hour interval,
followed by a further 100 mg/kg ZD6126; doses were given
intraperitoneally (i.p.).
[0209] Cisplatin (David Bull Laboratories) alone was dosed at 5
mg/kg i.p on day 0.
[0210] The combination treatment consisted of:
[0211] Day 0: ZD6126 100 mg/kg i.p., followed by a 2 hour interval,
followed by a further 100 mg/kg ZD6126 i.p; and cisplatin 5 mg/kg
given 10 minutes before first ZD6126 dose.
[0212] Days 2 and 4: ZD6126 100 mg/kg i.p., followed by a 2 hour
interval, followed by a further 100 mg/kg ZD6126 i.p..
[0213] The time for tumours to increase their geometric mean tumour
diameter, measured in 3 directions, by 3 mm was calculated and is
shown in Table 1 and the data displayed in FIG. 1.
1TABLE 1 Anti-tumour activity of ZD6126 and cisplatin in CaNT
tumours - study 1 Mean growth Time to increase mean delay (vs
Treatment diameter by 3 mm (days) control) - days Control 8.4, 8.2,
4.7, 7.2, 5.9 -- Cisplatin alone 10.0, 6.9, 9.2, 9.8 2.1 ZD6126
alone 16.4, 11.8, 11.6, 13.8 6.5 Cisplatin plus ZD6126 17.8, 16.1,
20.1, 19.3, 19.3 11.6
[0214] The tumour growth delay caused by the combination of ZD6126
and cisplatin was significantly (Mann-Whitney U-test) greater than
either cisplatin alone (P<0.01) or ZD6126 alone (P<0.05). The
growth delay from the combination was greater than the sum of the
growth delays from the individual treatments.
[0215] (ii) Second Study
[0216] ZD6126 alone was dosed on days 0, 4, 7 and 11 using a split
dose regimen of ZD6126 100 mg/kg i.p., followed by a 2 hour
interval, followed by a further 100 mg/kg ZD6126 i.p.. Cisplatin
alone was dosed at 5 mg/kg i.p on day 0 and day 7.
[0217] The combination treatment consisted of:
[0218] Days 0 and 7: ZD6126 100 mg/kg i.p., followed by a 2 hour
interval, followed by a further 100 mg/kg ZD6126 i.p.; cisplatin
given 10 minutes before first ZD6126 dose.
[0219] Days 3, 7 and 10: ZD6126 100 mg/kg i.p., followed by a 2
hour interval, followed by a further 100 mg/kg ZD6126 i.p..
[0220] The time for tumours to increase their geometric mean tumour
diameter, measured in 3 directions, by 3mm was calculated and is
shown in Table 2 and the data displayed in FIG. 2.
2TABLE 2 Anti-tumour activity of ZD6126 and cisplatin in CaNT
tumours - Study 2 Mean growth Time to increase mean delay (vs
Treatment diameter by 3 mm (days) control) - days Control 8.4, 8.2,
4.7, 7.2, 5.9 -- Cisplatin alone 15.7, 13.4, 12.5, 16.9 7.7 ZD6126
alone 16.4, 15.4, 17.8, 18.0, 16.5 9.9 Cisplatin plus ZD6126 27.4,
24.3, 30.6, 26.7, 29.9 20.9
[0221] The tumour growth delay caused by the combination of ZD6126
and cisplatin was significantly greater than either cisplatin alone
(P<0.01) or ZD6126 alone (P<0.01). The growth delay from the
combination was greater than the sum of the growth delays from the
individual treatments.
[0222] b) Calu 6 Tumour Model
[0223] In a second tumour model, Calu 6, the advantage of combining
ZD6126 and cisplatin (cis-Platinum(II)Diammine Dichloride--Sigma
P-4394) was confirmed. Athymic nude mice were implanted
subcutaneously with 1.times.10.sup.6 human Calu 6 tumour cells
(obtained from American Type Culture Collection, 10801 University
Boulevard, Manassas, Va. 20110-2209 Cat. no. Hm-56) and tumours
allowed to grow until they were approximately 9 mm in diameter.
Groups of 10 tumour bearing mice were then treated as follows:
[0224] ZD6126 alone was dosed 100 mg/kg i.p. on days 0, 1, 2, 3,
4.
[0225] Cisplatin alone was dosed 4 mg/kg i.p. on day 0.
[0226] In the combination arm cisplatin 4 mg/kg i.p. was dosed on
day 0, and ZD6126 100 mg/kg i.p. was dosed on days 1, 2, 3, 4 and
5. The results are shown in FIG. 3.
[0227] The combination of cisplatin and ZD6126 gave a growth delay
(time to reach 2.times. starting volume) of 20.5 days compared to
control tumours. This delay was significantly
(p<0.05-Mann-Whitney U-test) longer than either ZD6126 alone
(10.1 days) or cisplatin alone (6.0 days). The growth delay from
the combination was greater than the sum of the growth delays from
the individual treatments.
[0228] c) KHT Sarcoma Tumour Model
[0229] In the murine KHT sarcoma model (Lingyun Li, B. S. et al,
Int. J. Radiation Oncology Biol. Phys 42, 899-903, 1998) tumours
were treated with either 10 mg/kg cisplatin i.p. alone or 10 mg/kg
cisplatin plus ZD6126 (10-100 mg/kg i.p.), cisplatin given 1 hour
prior to ZD6126. The effects of the treatments on tumour cell
survival was assessed 24 hours later by excising the tumour,
disaggregating the cells and determining the number of colonies
formed after 10-14 days. Surviving fraction compared to untreated
cells was then determined. The results are shown in FIG. 4.
[0230] Cisplatin alone resulted in approximately 98% cell killing
(hatched area in FIG. 4) and this effect was enhanced in a dose
dependent fashion with ZD6126.
[0231] The mean percent cell survival at 20, 50 and 100 mg/kg was
0.4, 0.011 and 0.0012% respectively and thus these doses enhanced
cell kill over cisplatin alone by 5, 182 and 1667 fold
respectively.
[0232] ZD6126 in Combination with Ionising Radiation
[0233] a) CaNT Tumour Model
[0234] The activity of combining ZD6126 and radiation in the CaNT
tumour model was also investigated. Tumours were treated with
either radiation alone (15 Gy days 0 and 7), ZD6126 alone (single
dose of ZD6126 125 mg/kg i.p. on days 0, 1, 2, 3, 4, 7, 8, 9, 10
and 11), or a combination of both (15 Gy days 0 and 7, ZD6126 125
mg/kg i.p. on days 0, 1, 2, 3, 4, 7, 8, 9, 10 and 11). On the days
radiation and ZD6126 were administered together,,radiation
treatment was given 3 hours after ZD6126 administration. Radiation
was administered by placing the mice in lead boxes so that only the
tumour bearing portion of the rear dorsum was exposed to a
horizontal X-ray beam (Sheldon and Hill, B J C, 35, 795-808, 1997).
Mice were irradiated with 240 kV X-rays at a dose rate of 3.6
Gy/min.
[0235] The time for tumours to increase their geometric mean tumour
diameter, measured in 3 directions, by 3mm was calculated and is
shown in Table 3 and the data displayed in FIG. 5.
3TABLE 3 Anti-tumour effects of ZD6126 and radiation in CaNT
tumours Mean growth Time to increase mean delay (vs Treatment
diameter by 3 mm (days) control) - days Control 6.0, 8.0, 6.7, 5.1,
6.3, 6.6, -- 5.1, 6.4 Radiation alone 47.3, 53.0, 31.5, 54.3, 37.0
38.3 ZD6126 alone 15.6, 17.7, 14.1, 14.6, 14.7 9.1 Radiation and
ZD6126 49.0, 58.0, 57.5, 63.5, 55.6 50.4
[0236] The tumour growth delay caused by the combination of ZD6126
and radiation was significantly greater than either radiation alone
(P<0.05) or ZD6126 alone (P<0.01). The growth delay from the
combination was greater than the sum of the growth delays from the
individual treatments.
[0237] b) KHT Sarcoma Tumour Model
[0238] The murine KHT sarcoma grown in C3H mice was also used to
confirm the advantage of combining ZD6126 and radiation. Tumours
were treated with either radiation alone (0, 5, 10, 15 or 20 Gy
single dose), ZD6126 100 mg/kg i.p., or radiation followed 1 hour
later by ZD6126 100 mg/kg i.p.. The effects of either radiation
alone, ZD6126 alone or the combination on tumour cell survival was
assessed 24 hours later by excising the tumour, disaggregating the
cells and determining the number of colonies formed after 10-14
days. Surviving fraction compared to untreated cells was then
determined. The results are shown in FIG. 6.
[0239] ZD6126 alone (100 mg/kg) killed approximately 97-98% of the
tumour cells and enhanced the level of tumour killing at all 3
radiation doses tested. Combining ZD6126 with radiation doses of 5,
10 or 15 Gy result in 100-200 fold enhancement in cell killing
(ZD6126 alone with no radiation enhanced cell killing by 40 fold
over controls)--Table 4.
4TABLE 4 Anti-tumour effects of ZD6126 and radiation in KHT Sarcoma
Plus ZD6126 ZD6126 Radiation dose(Gy) % cell survival % cell
survival Enhancement 0 100 2.5 40 5 20 0.16 125 10 1.5 0.015 100 15
0.35 0.0016 219 20 0.05 ND -- ND = not determined
[0240] ZD6126 in Combination with Paclitaxel
[0241] a) FaDu Tumour Model
[0242] In a third tumour model 5.times.10.sup.5FaDu cells (human
squamous cell carcinoma of the pharynx) were implanted onto the
rear dorsum of 12-16 week old, female SCID mice. When the tumours
had become established they were excised and cut into small tumour
fragments approximately 1 mm.sup.3. These fragments were implanted
subcutaneously into further SCID mice. Once these tumours had
become established (approximately 6 mm diameter) mice were treated
with either a single dose of ZD6126 (125 mg/kg i.p.) alone, a
single dose of paclitaxel (Taxol-BMS) (15 or 30 mg/kg i.p.) alone
or the combination of a single dose of paclitaxel (15 mg/kg i.p.)
and ZD6126 (125 mg/kg i.p.), paclitaxel being given 15 minutes
before ZD6126.
[0243] The time for tumours to increase their geometric mean tumour
diameter, measured in 3 directions, by 3 mm was calculated and is
shown in Table 5 and the data displayed in FIG. 7.
5TABLE 5 Anti-tumour effects of ZD6126 and Paclitaxel in FaDu
tumours Mean growth Time to increase mean delay (vs Treatment
diameter by 3 mm (days) control) - days Control 6.0, 5.0, 5.0, 5.4,
5.8, 7.0, -- 6.8, 5.2, 6.8 Paclitaxel (15 mg/kg) alone 11.2, 10.8
5.1 ZD6126 alone 8.9, 12.5, 12.0, 7.3 4.3 Paclitaxel plus ZD6126
22.4, 19.6, 18.1 14.1
[0244] The tumour growth delay caused by the combination of ZD6126
and paclitaxel was significantly greater than giving ZD6126 alone
(P<0.05). The growth delay from the combination was greater than
the sum of the growth delays from the individual treatments.
[0245] Cell Survival Assay
[0246] The activity of ZD6126 administered in split doses may be
demonstrated by the following cell survival assay.
[0247] In vivo cell survival was measured using an excision assay
(D J Chaplin et al., Anticancer Research 19: 189-196 (1999)).
[0248] For each of the assays a) and b) below, the surviving
fraction of tumour cells was determined as follows:
[0249] Tumours were excised at about 18 hours after treatment,
weighed and disaggregated for 1 hour at 37 degrees Celsius in an
enzyme cocktail containing 1 mg/ml pronase, 0.5 mg/ml DNAase and
0.5 mg/ml collagenase. Haemocytometer counts of trypan
blue-excluding cells were made and viable cells seeded in
appropriate concentrations to yield about 50 colonies/dish after in
vitro incubation. Heavily irradiated feeder cells (V79 cells) were
used at a concentration of 25,000/ml to support the growth of the
surviving CaNT cells. The data were calculated as surviving
fraction per gram of tumour.
[0250] a) CaNT Tumour Model: Effect of Dosage Interval
[0251] In the murine adenocarcinoma CaNT tumour model grown in
female CBA mice (Hill, S. A. et al, Int. J. Cancer 63, 119-123,
1995) administering ZD6126 in divided doses resulted in an improved
anti-tumour effect compared to ZD6126 administered as a single dose
as measured by surviving fraction of tumour cells. See FIG. 8.
[0252] Methodology
[0253] Single Dose
[0254] ZD6126 was administered as a single dose of 200 mg
intra-peritoneally (i.p.) in saline with a small amount of 1%
sodium carbonate added to aid the dissolution of ZD6126.
[0255] Divided Doses
[0256] ZD6126 was dosed using a split dose regimen of 100 mg/kg
ZD6126, followed by a time interval, followed by a further 100
mg/kg ZD6126; doses were given intraperitoneally (i.p.) in saline
with a small amount of 1% sodium carbonate added to aid the
dissolution of ZD6126.
[0257] The time intervals used were 1, 2, 3, 4 and 6 hours.
[0258] Surviving fraction per gram of tumour was determined as
described above and plotted as shown in FIG. 8.
[0259] Two doses of 100 mg/kg separated by 2, 3 or 4 hours were
significantly more effective in this model than a single 200 mg/kg
dose.
[0260] b) CaNT Tumour Model: Effect of Dosage Interval and Split
Dose Proportions
[0261] In the murine adenocarcinoma CaNT tumour model grown in
female CBA mice (Hill, S. A. et al, Int. J. Cancer 63, 119-123,
1995) administering ZD6126 in divided doses 2 hours apart resulted
in an improved anti-tumour effect, as measured by surviving tumour
cell fraction, compared to ZD6126 administered as a single dose.
This improved effect varied with the proportion of total dose given
in the first and second doses. See FIG. 9.
[0262] Methodology
[0263] Single Dose
[0264] ZD6126 was administered as a single dose of 200 mg
intra-peritoneally (i.p.) in saline with a small amount of 1%
sodium carbonate added to aid the dissolution of ZD6126.
[0265] Divided Doses
[0266] ZD6126 was dosed using split dose regimens of:
[0267] i) 25 mg/kg ZD6126, followed by a 2 hour interval, followed
by a further 175 mg/kg ZD6126;
[0268] ii) 50 mg/kg ZD6126, followed by a 2 hour interval, followed
by a further 150 mg/kg ZD6126;
[0269] iii) 100 mg/kg ZD6126, followed by a 2 hour interval,
followed by a further 100 mg/kg ZD6126;
[0270] iv) 150 mg/kg ZD6126, followed by a 2 hour interval,
followed by a further 50 mg/kg ZD6126;
[0271] v) 175 mg/kg ZD6126, followed by a 2 hour interval, followed
by a further 25 mg/kg ZD6126;
[0272] All doses were given intraperitoneally (i.p.) in saline with
a small amount of 1% sodium carbonate added to aid the dissolution
of ZD6126.
[0273] The anti-tumour effect, as measured by surviving fraction of
tumour cells, was greater with divided doses of ZD6126 than with a
single dose of 200 mg/kg ZD6126. This greater effect was
significant when divided doses of ZD6126 were administered
according to i), iii) or iv) above. The best effect was seen with
equal split doses, ie according to iii) above.
* * * * *